Torsemide - Demadex
DEMADEX is indicated for the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Use of torsemide has been found to be effective for the treatment of edema associated with chronic renal failure.Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
DEMADEX intravenous injection is indicated when a rapid onset of iuresis is desired or when oral administration is impractical.
DEMADEX is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents.
Dosage and Administration
DEMADEX tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary.
Because of the high bioavailability of DEMADEX, oral and intravenous doses are therapeutically equivalent, so patients may be switched to and from the intravenous form with no change in dose. DEMADEX intravenous injection should be administered either slowly as a bolus over a period of 2 minutes or administered as a continuous infusion.
If DEMADEX is administered through an IV line, it is recommended that, as with other IV injections, the IV line be flushed with Normal Saline (Sodium Chloride Injection, USP) before and after administration. DEMADEX injection is formulated above pH 8.3. Flushing the line is recommended to avoid the potential for incompatibilities caused by differences in pH which could be indicated by color change, haziness or the formation of a precipitate in the solution.
If DEMADEX is administered as a continuous infusion, stability has been demonstrated through 24 hours at room temperature in plastic containers for the following fluids and concentrations:
200 mg DEMADEX (10 mg/mL) added to:
250 mL Dextrose 5% in water
250 mL 0.9% Sodium Chloride
500 mL 0.45% Sodium Chloride
50 mg DEMADEX (10 mg/mL) added to:
500 mL Dextrose 5% in water
500 mL 0.9% Sodium Chloride
500 mL 0.45% Sodium Chloride
Before administration, the solution of DEMADEX should be visually inspected for discoloration and particulate matter. If either is found, the ampul should not be used.
Congestive Heart Failure
The usual initial dose is 10 mg or 20 mg of once-daily oral or intravenous DEMADEX. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.
Chronic Renal Failure
The usual initial dose of DEMADEX is 20 mg of once-daily oral or intravenous DEMADEX. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.
The usual initial dose is 5 mg or 10 mg of once-daily oral or intravenous DEMADEX, administered together with an aldosterone antaagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 40 mg have not been adequately studied.
Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
The usual initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should be added to the treatment regimen.
105 (for 5 mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite side, the tablet is debossed with 5, 10, 20, or 100 to indicate the dose.
DEMADEX for intravenous injection is supplied in clear ampuls containing 2 mL (20 mg, NDC 0004-0267-06) or 5 mL (50 mg, NDC 0004-0268-06) of a 10 mg/mL sterile solution. The ampuls are supplied in boxes of 10.
At the time of approval, DEMADEX had been evaluated for safety in approximately 4000 subjects: over 800 of these subjects received DEMADEX for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received DEMADEX during United States-based trials in which 274 other subjects received placebo.
The reported side effects of DEMADEX were generally transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects occurred in 3.5% of United States patients treated with DEMADEX and in 4.4% of patients treated with placebo. In studies conducted in the United States and Europe, discontinuation rates due to side effects were 3.0% (38/1250) with DEMADEX and 3.4% (13/380) with furosemide in patients with congestive heart failure, 2.0% (8/409) with DEMADEX and 4.8% (11/230) with furosemide in patients with renal insufficiency, and 7.6% (13/170) with DEMADEX and 0% (0/33) with furosemide in patients withcirrhosis.
The most common reasons for discontinuation of therapy with DEMADEX were (in descending order of frequency) dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricemia, hypokalemia, excessive thirst, hypovolemia, impotence, esophageal hemorrhage, anddyspepsia. Dropout rates for these adverse events ranged from 0.1% to 0.5%.
The daily doses of DEMADEX used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 days, with a median of 41 days. Of the side effects listed in the table, only "excessive urination" occurred significantly more frequently in patients treated with DEMADEX than in patients treated with placebo. In the placebo-controlled hypertension studies whose design allowed side-effect rates to be attributed to dose, excessive urination was reported by 1% of patients receiving placebo, 4% of those treated with 5 mg of daily DEMADEX, and 15% of those treated with 10 mg. The complaint of excessive urination was generally not reported as an adverse event among patients who received DEMADEX for cardiac, renal, or hepatic failure.
Serious adverse events reported in the clinical studies for which a drug relationship could not be excluded were atrial fibrillation, chest pain, diarrhea, digitalis intoxication, gastrointestinal hemorrhage, hyperglycemia, hyperuricemia, hypokalemia, hypotension, hypovolemia, shunt thrombosis, rash,rectal bleeding, syncope, and ventricular tachycardia.
Angioedema has been reported in a patient exposed to DEMADEX who was later found to be allergic to sulfa drugs.
Of the adverse reactions during placebo-controlled trials listed without taking into account assessment of relatedness to drug therapy, arthritis and various other nonspecific musculoskeletal problems were more frequently reported in association with DEMADEX than with placebo, even though gout was somewhat more frequently associated with placebo. These reactions did not increase in frequency or severity with the dose of DEMADEX. One patient in the group treated with DEMADEX withdrew due to myalgia, and one in the placebo group withdrew due to gout.
In patients with essential hypertension, DEMADEX has been administered together with beta-blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive heart failure, DEMADEX has been administered together with digitalis glycosides, ACE inhibitors, and organic nitrates. None of these combined uses was associated with new or unexpected adverse events.
Torsemide does not affect the protein binding of glyburide or of warfarin, theanticoagulant effect of phenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (a vasodilator/beta-blocker). In healthy subjects, coadministration of DEMADEX was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the AUC. However, clinical experience indicates that dosage adjustment of either agent is not required.
Because DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when DEMADEX is concomitantly administered. Also, although possible interactions between torsemide and nonsteroidal anti-inflammatory agents (including aspirin) have not been studied, coadministration of these agents with another loop diuretic (furosemide) has occasionally been associated with renal dysfunction.
The natriuretic effect of DEMADEX (like that of many other diuretics) is partially inhibited by the concomitant administration of indomethacin. This effect has been demonstrated for DEMADEX under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day).
The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine or spironolactone. Coadministration of digoxin is reported to increase the area under the curve for torsemide by 50%, but dose adjustment of DEMADEX is not necessary.
Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If DEMADEX and cholestyramine are used concomitantly, simultaneous administration is not recommended.
Coadministration of probenecid reduces secretion of DEMADEX into the proximal tubule and thereby decreases the diuretic activity of DEMADEX.
Other diuretics are known to reduce the renal clearance of lithium, inducing a high risk of lithium toxicity, so coadministration of lithium and diuretics should be undertaken with great caution, if at all. Coadministration of lithium and DEMADEX has not been studied.
Other diuretics have been reported to increase the ototoxic potential of aminoglycoside antibiotics and of ethacrynic acid, especially in the presence of impaired renal function. These potential interactions with DEMADEX have not been studied.